1. Field of the Invention
The invention relates to a method for enhancing the immune function of leukocytes.
2. Description of the Related Art
Leukocytes play an important role in the immune system. They have the abilities to recognize and remove foreign substances so as to defend a subject from pathogens. Furthermore, leukocytes use various mechanisms to identify and remove abnormal molecules newly synthesized in leukocytes so as to avoid their harmful effects on cells (Ellgaard, L., Molinari, M., and Helenius, A; 1999. Setting the Standards: Quality Control in the Secretory Pathway. Science 286, 1882-1888).
Mutations or deficiencies in genes of leukocytes have been observed to lead to many congenital immune deficiencies or dysfunctions. Mutant leukocyte genes may encode erroneous proteins which exhibit abnormal leukocyte functions and lead to immune deficiencies or dysfunctions. Generally, products of mutant genes are often detected at the early stage of the biosynthetic process of proteins. The quality control mechanism in cells will be triggered wherein premature proteins translated by mutant genes are degraded by enzymes and removed from cells. Previous investigations have revealed that the degradation of premature proteins may occur at the transcription or translation stage (Ellgaard et al., 1999, Supra). For complex proteins, mutant peptides will be retained in the endoplasmic reticulum by molecular chaperons which lead to degradation pathways in the cytoplasm. This molecular quality control mechanism can avoid the wasteful production of useless or even harmful mutant proteins from valuable resources in cells which harbor mutant genes. On the other hand, since the mechanism is initiated by the mutations, mutant proteins which still exhibit some functions are removed as well as the useless or harmful molecules. As for X-linked or homozygous genes, their removal may cause severe genetic diseases.
For example, chronic granulomatous disease (CGD) is a hereditary immunodeficiency caused by deficiencies in reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of phagocyte. NADPH oxidase is composed of flavocytochrome b558, formed by cell membrane-bound gp91-phox and p22-phox, and the cytoplasmic proteins p40-phox, p47-phox and p67-phox. Leukocyte NADPH oxidase requires non-peptide cofactors of heme (the prosthetic group) and cofactor flavin adenine dinucleotide (FAD) to from a functional complex. If mutations occur at domains of the enzyme which bind to these cofactors, or at other domains, the enzyme will fail to function in the catalytic production of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. Young patients may hence suffer from recurrent microbial infections. (See Rae, J., Newburger, P. E., Dinauer, M. C., Noack, D., Hopkins, P. J. and Curnutte, J. T.; 1995 X-Linked Chronic Granulomatous Disease: Mutations on the CYBB Gene Encoding the gp91-phox Component of Respiratory-Burst Oxidase. Am J. Hum. Genet. 62, 1320-1331) Many publications have disclosed that mutations with respect to the genes gp91-, p22-, p67-, and p47-phox will cause chronic granulomatous diseases (Heyworth, P. G., curnutte, J. T., Noack, D. and Cross, A. R.; 1997. Hematologically Important Mutations: X-linked Chronic Granulomatous Disease-an Update. Blood Cells Mol. Dis. 23, 443-450; Roos, D., de Boer, M., Kuribayashi. F. Meischl, C., Weeing, R. S., Segal, A. W., Ahlin, A., nemet, K., Hossle, J. P., Bernatowska-Matuszkiewicz, E. and Middleton-Price, H; 1996. Mutations in the X-linked and Autosomal Recessive Forms of Chronic Granulomatous Disease. Blood 87, 1663-1681; Noack, D., Rae, J., Cross, A. R., Ellis, B. A., Newburger, P. E., Curnutte, J. T. and Heyworth, P. G.; 2001. Autosomal Recessive Chronic Granulomatous Disease Caused by Deficiencies in NCF-1, the Gene Encoding the Phagocyte p47-phox: Mutations not Arising in the NCF-1 Pseodogenes. Blood 97, 305-311). X-linked chronic granulomatous disease (X91 CGD) is further reported. Molecular quality control mechanism in the nucleus or endoplasmic reticulum monitors the production of proteins synthesis destined for plasma membrane and endocytic organelles (Lin, S. J., Huang, Y. F., Chen, J. Y., Heyworth, P. G., Noack, D., Wang, J. Y., Lin, C. Y., Chiang, B. L., Yang, C. M., Liu, C. C. and Shieh, C. C.; 2002. Molecular quality control machinery contributes to the leukocyte NADPH oxidase deficiency in chronic granulomatous disease. Biochim. Biophys. Acta 1586, 275-286).
Current methods for treating deficient leukocyte function include bone marrow transplantation, gene therapy and cytokine therapy. Although bone marrow transplantation has been well developed for several years, its application is still restricted because bone marrow cell donors with a matching genotype are not available in many cases. Furthermore, recipients are at the risk of graft versus host disease (GvHD) and being infected by donors. Gene therapy involves the introduction of a foreign DNA sequences that replace the defective DNA structure of cells. However, this treatment is still hampered by the complications including malignant transformation and septic shock. Due to safety concerns, the application of gene therapy is on hold. Currently, cytokine therapy is only applied to a few diseases. Such therapies often fail to sufficiently restore the function of cells expressing mutant proteins and are very costly. In addition, because the deficient or mutant genes are often expressed only in specific sites, such as in blood cells, severe side-effects may occur when the drugs are administered systemically.
Therefore, a method for enhancing the immune function of leukocytes bearing mutant proteins without severe side effects is needed in the art.